Clotrimazole, an antimycotic drug, inhibits the sarcoplasmic reticulum calcium pump and contractile function in heart muscle

Clotrimazole (CLT), an antimycotic drug, has been shown to inhibit proliferation of normal and cancer cell lines and its systemic use as a new tool in the treatment of proliferative disorders is presently under scrutiny (Benzaquen, L. R., Brugnara, C., Byers, H. R., Gattoni-Celli, S., and Halperin, J. A. (1995) Nature Med. 1, 534-540). The action of CLT is thought to involve depletion of intracellular Ca2+ stores but the underlying mechanism has not been defined. The present study utilized membrane vesicles of rabbit cardiac sarcoplasmic reticulum (SR) to determine the mechanism by which CLT depletes intracellular Ca2+ stores. The results revealed a strong, concentration-dependent inhibitory action of CLT on the ATP-energized Ca2+ uptake activity of SR (50% inhibition with approximately 35 microM CLT). The inhibition was of rapid onset (manifested in <15 s), and was accompanied by a 7-fold decrease in the apparent affinity of the SR Ca2+-ATPase for Ca2+ and a minor decrement in the enzyme's apparent affinity toward ATP. Exposure of SR to CLT in the absence or presence of Ca2+ resulted in irreversible inhibition of Ca2+ uptake demonstrating that the Ca2+-bound and Ca2+-free conformations of the Ca2+-ATPase are CLT-sensitive. Introduction of CLT to the reaction medium subsequent to induction of enzyme turnover with Ca2+ and ATP resulted in instantaneous cessation of Ca2+ transport indicating that an intermediate enzyme species generated during turnover undergoes rapid inactivation by CLT. The inhibition of Ca2+ uptake by CLT was accompanied by inhibition of Ca2+-stimulated ATP hydrolysis and Ca2+-induced phosphoenzyme intermediate formation from ATP in the ATPase catalytic cycle. Phosphorylation of the Ca2+-deprived enzyme with Pi in the reverse direction of catalytic cycle and Ca2+ release from Ca2+-preloaded SR vesicles were unaffected by CLT. It is concluded that CLT depletes intracellular Ca2+ stores by inhibiting Ca2+ sequestration by the Ca2+-ATPase. The mechanism of ATPase inhibition involves a drug-induced alteration in the Ca2+-binding site(s) resulting in paralysis of the enzyme's catalytic and ion transport cycle. CLT (50 microM) caused marked depression of contractile function in isolated perfused, electrically paced rabbit heart preparations. The contractile function recovered gradually following withdrawal of CLT from the perfusate indicating the existence of mechanisms in the intact cell to inactivate, metabolize, or clear CLT from its target site.     

Biochemical and biological characterizations and ribotyping of Actinomyces pyogenes and Actinomyces pyogenes-like organisms from liver abscesses in cattle

Actinomyces pyogenes is the second most frequently encountered pathogen, next only to Fusobacterium necrophorum, in liver abscesses of feedlot cattle. Ninety-one isolates, presumptively identified as A. pyogenes, isolated from liver abscesses of cattle were studied. Biochemical characteristics determined by the API 20 Strep kit were similar to those reported previously for A. pyogenes isolated from other infections, except that 18% of isolates hydrolyzed esculin. Nine isolates that resembled A. pyogenes in morphology and in certain biochemical characteristics, but fermented mannitol and/or raffinose, were called A. pyogenes-like (APL) organisms. The five antimicrobial agents, bacitracin, chlortetracycline, oxytetracycline, tylosin, and virginiamycin were inhibitory to all strains of A. pyogenes and APLs. Generally, APL organisms had higher mean hemolytic and leukotoxic activities than A. pyogenes. All isolates of A. pyogenes and APLs produced proteases and neuraminidases. Ribotyping with endonucleases, including BstEII, ClaI, EcoRI, EcoRV, HaeIII, MboI, PvuII, SalI, and SmaI alone or in combinations, showed considerable genetic heterogeneity in both A. pyogenes and APLs. No specific ribopattern characteristic of each group was observed with any of the endonuclease used. The origin of A. pyogenes and APLs and the relative importance of APLs in causing liver abscesses in feedlot cattle are not known.     

Influence of composition and curing on drying shrinkage of aerated concrete

The process of drying of many materials is accompanied by dimensional changes, which induce cracks in the structure. This phenomenon is particularly significant in acrated concrete owing to its high total porosity and specific surface of pores. The factors influencing drying shrinkage of aerated concrete are widely different from that of normal concrete because of the presence of coarse aggregates in the latter. This paper discusses the results of statistically designed experiments conducted to ascertain the influence of composition on the drying shrinkage of non-autoclaved and autoclaved aerated concrete. Detailed single factor experiments were conducted to assess the influence of basic constituents of the mix on drying shrinkage whereas fractional factorial experiments were used for the interaction effects and the influence of some additives. It was observed that increase in lime-cement ratio and fly ash content increases drying shrinkage. Significant shrinkage reduction is obtained by autoclaving, suggesting that drying shrinkage is predominantly a function of the physical structure of the hydration product.     

Elastic buckling of perforated plates under shear

Finite element studies aimed at computing the buckling coefficient for plates containing cut-outs and subjected to shear are reported. The cases considered are:

1. 1. Square and rectangular plates with central circular cut-outs.

2. 2. Square plates with centrally placed rectangular cut-outs.

3. 3. Square plates with eccentrically placed circular cut-outs.

4. 4. Square plates with reinforced circular cut-outs.

5. 5. Square plates with reinforced rectangular cut-outs.

Simply supported plates as well as clamped plates have been studied and approximate formulae for the use of designers have been suggested for the practical cases where the hole dimension is generally not greater than half the width of the plate.     

Structural modification of zirconia and its influence on the catalytic activity

X-ray diffraction, differential thermal analysis and specific surface area measurements have been employed to understand the structural properties of ZrO₂ and sulphate-modified ZrO₂ calcined at different temperatures. Calcination facilitates the transformation of ZrO₂ from cubic to monoclinic phase. Addition of SO₄ ion to Zr(OH)₄ helps to retain the cubic phase up to 550 °C, and to maintain the surface area through a surface complex formation mechanism. The modified ZrO₂ acts as a superacid catalyst and enhances the vapour-phase aniline alkylation.     

Thermal Stability, Phase Evolution, and Crystallization in Si-B-C-N Ceramics Derived from a Polyborosilazane Precursor

Amorphous Si-B-C-N ceramic powder samples obtained by thermolysis of boron-modified polysilazane, {B[C₂H₄Si(H)NH]₃} _n , were isothermally annealed at different temperatures (1400–1800°C) and hold times (3, 10, 30, and 100 h). A qualitative and semiquantitative analysis of the crystallization behavior of the materials was performed using X-ray diffraction (XRD). The phase evolution was additionally followed by ¹¹B and ²⁹Si MAS NMR as well as by FT-IR spectroscopy in transmission and diffuse reflection (DRIFTS) modes. Bulk chemical analyses of selected samples were performed to determine changes in the chemistry/phase composition of the materials. It was observed that silicon carbide is the first phase to nucleate around 1400–1500°C, whereas silicon nitride nucleates at and above 1700°C. Crystallization accelerates with increasing annealing temperature and proceeds with increasing annealing time. Furthermore, the surface area of the powders strongly influences the thermal stability of silicon nitride and thus controls overall chemical and phase composition of the materials on thermal treatment.     

Plasma-Sprayed Ceramic Reaction Couples

In preparing specimens for studying reaction kinetics, it is essential to ensure proper contact between couple end-members. In the present work, reaction couples were prepared by spraying layers of the end-member materials over one another. This method has many advantages, including precise control over the properties of the end-members.     

Desalination of brackish water by electrodialysis

The performance of an electrodialysis unit comprising interpolymer type cation and anion-exchange membranes developed in this institute in single-stage and two-stage operation for desalting of brackish waters having different total dissolved solids has been studied highlighting the energy requirement and pressure drop under different conditions. For higher salinity waters, a two-stage reduction is advantageous with lower power requirements and power index. The results will be useful for design and installation of ED plants in brackish water sectors.     

Effect of varietal or subvarietal alterations on the high order compositeness status of fats from the same biological species. The glyceride structures of threeMyristica malabarica mace fats

Mace fats from three morphologically indistinguishable subvarieties ofMyristica malabarica and from the same geographical area were investigated for high order compositeness (HOC) indices (2,3) by the azelaoglyceride analysis technique (1). The fats had saturated acid contents of 36.5, 43.7, and 49.8% by molecules, and the differences in the component acid compositions were adequate to establish differences in the source of biological origin in all three cases. The subvarieties thus showed uncommonly large alterations in fat metabolism genes for any particular biological species so far reported. All three fats were of the GS₃ nil type, and the GS₂U values of the HOC indices were +1.9, +2.6, and +1.8 respectively. These differences were within the limits of experimental error, and all three fats showed the same HOC index in spite of large differences in component acids. Subvarietal alterations involving large changes in component acids can hence take place without altering the HOC indices. This is perhaps possible only if there are separate genes controlling HOC in the fat metabolism genes complex, and these are not necessarily affected in the same manner by factors which produce changes in the genes that control component acid compositions. HOC is thus seen to be a new and independent structural feature of natural fats, which, in the future, has to be considered along with theories of bio-esterification to give complete explanations for triglyceride structure.